The Role of Alpha and Beta Platelet-Derived Growth Factor Receptor in the Vascular Response to Injury in Nonhuman Primates

Abstract

Abstract-Restenosis remains a significant clinical problem associated with mechanical interventional procedures for arterial revascularization or repair, including coronary angioplasty and stenting. Studies with rodents have established that platelet-derived growth factor (PDGF), a potent chemotactic and mitogenic agent for vascular smooth muscle cells, is a key mediator of lesion formation after vascular injury. To further explore this hypothesis in a more clinically relevant model, neutralizing monoclonal antibodies (mAbs) were used to examine the effect of selective inhibition of alpha or beta PDGF receptor (PDGFR) on neointima formation in nonhuman primates. Carotid arteries were injured by surgical endarterectomy and femoral arteries by balloon catheter dilatation. Immunostaining revealed that both injuries induced cell proliferation and the upregulation of beta PDGFR but not alpha PDGFR. By 7 days after injury, beta PDGFR staining was limited to the luminal region of the media, the small areas of neointima, and the adventitia. Nearly all bromodeoxyuridine-positive cells were found in these regions as well. After 30 days, a concentric neointima that stained strongly for beta PDGFR had formed in the carotid and femoral arteries. Treatment of baboons with anti-beta PDGFR mAb 2A1E2 for 6 days after injury reduced the carotid artery and femoral artery lesion sizes by 37% (PϽ0.05) and 48% (PϽ0.005), respectively, when measured at 30 days. Under the same conditions, treatment with anti-alpha PDGFR mAb 2H7C5 had no effect. These findings suggest that PDGF mediates neointima formation through the beta PDGFR, and that antagonism of this pathway may be a promising therapeutic strategy for reducing clinical restenosis.

Interleukin-1β Inhibits Expression of p21(WAF1/CIP1) and p27(KIP1) and Enhances Proliferation in Response to Platelet-Derived Growth Factor-BB in Smooth Muscle Cells

“…4,5 In contrast, blockade of PDGF receptor-␣ (PDGFR␣) has no effect on intimal hyperplasia in that model. 5 The PDGF family consists of 4 peptides, PDGF-A, PDGF-B, and the recently described PDGF-C 6,7 and PDGF-D chains.…”

“…4,5 In contrast, blockade of PDGF receptor-␣ (PDGFR␣) has no effect on intimal hyperplasia in that model. 5 The PDGF family consists of 4 peptides, PDGF-A, PDGF-B, and the recently described PDGF-C 6,7 and PDGF-D chains. 8,9 PDGF binds as a homodimer or heterodimer, and the PDGF receptor ligands identified so far are PDGF-AA, PDGF-BB, PDGF-CC, PDGF-DD, and PDGF-AB dimers.…”

Role of platelet-derived growth factors in physiology and medicine

“…A number of different gain-and loss-of-function experiments suggest a role for PDGF in animal models of atherosclerosis. Specifically, in different animal models of acute arterial injury by balloon catheterization, neointimal SMC accumulation was reduced by the administration of various PDGF pathway inhibitors, including neutralizing PDGF (AB) antibodies (Ferns et al 1991;Lewis et al 2001), PDGF-B aptamers (Leppänen et al 2000), PDGFR kinase inhibitors (Banai et al 1998;Yamasaki et al 2001), and PDGFR-neutralizing antibodies (Giese et al 1999;Hart et al 1999). Restenosis following angioplasty of atherosclerotic vessels in minipigs (Bilder et al 1999) and chronic cardiac transplant rejection-induced atherosclerosis in rats (Sihvola et al 1999) were also inhibited by PDGFR-blocking kinase inhibitors.…”

Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Forms a Signaling Complex with Platelet-derived Growth Factor Receptor-β in Endosomes and Regulates Activation of the MAPK Pathway

“…Thus, enhanced activation of the PDGF signaling pathway is implicated in the development of atherosclerosis, vascular injury-induced restenosis, angiogenesis, and fibrosis (5). A significant contribution of PDGF to vascular remodeling was confirmed by studies demonstrating that neointimal smooth muscle cell accumulation was reduced by administration of either PDGF-B (6) or PDGFR neutralizing antibodies (7,8) during vascular injury induced by balloon catheterization. Conversely, expression of PDGF-B in the vasculature leads to increased SMC proliferation and intima thickening (9).…”